The trillions of microorganisms inhabiting the human gastrointestinal tract (gut microbiota) contribute importantly to energy balance, but their net effect on energy gain and expenditure is shaped by diet. While the impacts of altering diet quantity or composition have been studied, the impacts of processing a given diet by common methods like cooking or grinding remain unknown. A large literature indicates that food processing enhances energy gain by increasing the proportion of dietary carbohydrates that are assimilated in the small intestine. This reduces the fraction of nutrients passing undigested into the colon, where the densest microbial communities reside, and could thus be expected to limit the microbial contribution to energy gain. However preliminary data reveal dramatic impacts of a processed carbohydrate-rich plant diet on gut microbial ecology that instead favor microbial taxa known to stimulate host adiposity. These results, combined with those of prior studies, suggest that energy gain reflects complex interactions between host, dietary and microbial factors. This goal of this research program is to characterize the contributions of the gut microbiota to energy gain on processed diets. Benefiting from insight achieved in the comparison of conventional and gnotobiotic (germ-free or colonized) mice, the studies proposed will address three specific aims: Aim 1: Test alternative hypotheses for the impact of food processing on gut microbial communities, focusing on the roles of processing in increasing bioavailability and deactivating foodborne xenobiotics; Aim 2: Interrogate the microbial promotion of energy gain on processed diets through gnotobiotic experiments involving colonization and gut microbiota transplantation; and Aim 3: Extend work to other food substrates that exhibit distinct properties when processed, enabling tests of other putative mechanisms for the microbial promotion of energy gain. These studies will address novel mechanisms of host-microbial interaction, increasing our understanding of the ecological determinants of human health. Such work holds clinical promise because robust knowledge of microbial impacts on host physiology could lead to new treatments for disease via manipulation of the gut microbiota or its downstream host targets. Notably, food processing is an especially attractive possibility for intervention, being a ubiquitous and readily modifiable feature of the human diet. These advantages make this research program a fertile foundation for subsequent work involving a wide range of substrates and processing methods, more detailed analysis of host-microbial interactions, and eventual translation to human subjects.